The potential inhibitory effects of anti-oxidative agents, including glutathione (GSH) and its precursors, against human immunodeficiency virus type I (HIV-1), have been investigated over the last several years. In early studies, reducing compounds such as D-penicillamine, 2,3 dimercapto-1-propanol and N-acetylcysteine (NAC) were found to inhibit HIV-1 long terminal repeat (LTR)-directed viral gene transcription (FEBS Letters 1988; 236: 282-286, AIDS Res Human Retroviruses 1990; 7: 919-927, Proc Nati Acad Sci USA 1990; 87: 48844888, Proc Natl Acad Sci USA 1991; 88: 986-990). In parallel with these initial basic studies, reduction of GSH levels in plasma, peripheral blood cells, and lung epitheliallining fluid has been reported in HIV-1-infected-individuals (Biol Chem Hoppe-Seyler 1989; 370: 101-108, AIDS Res Human Retroviruses 1992; 2: 305-311, Lancet 1989; 11: 1294-1298). GSH is known not only as a major intracellular anti-oxidant, but also as an modulator of the immune system (J Immunol 1985; 135: 2740-2747). Hence, altering the GSH deficiency of HIV1-infected individuals by glutathione precursors has been hypothesized to be one of the rational therapeutic strategies to prevent HIV-1 propagation in vivo (AIDS Res Human Retroviruses 1992; 8: 209-215, Blood 1995; 86: 258-267, Blood 1996; 87: 4746-4753). In this manner, the inhibitory effects of GSH pro-drugs, such as NAC, against HIV-1 have been further characterized. These compounds have been shown to be capable of inhibiting HIV-1 gene transcription, which is induced by tumor necrosis factor alpha (TNF-.alpha.) or phorbol 12-myristate 13-acetate (PMA), from latent proviruses. This is a model for the cellular latent stage of HIV-1 infection (Proc Natl Acad Sci USA 1991; 88: 986-990, Cell 1990; 61: 1271-1276). Of note, in a recent report, enhancement of HIV-1 growth by NAC was described in peripheral blood mononuclear cells (PBMC) (AIDS 1997; 11: 33-41).
Recent studies have demonstrated that the replication of HIV-
I is continuously active in lymphoreticular tissues (Nature 1993; 362:355-358, Nature 1993; 312: 359-362). Therefore; it may be difficult to significantly alter HIV-1 infection only by keeping latent HIV-1 proviruses in a non-replicative state, without shutting off the massive virus production from so-called late-phase infected cells and subsequent further rounds of infection. It has been implied that, in order to slow down the progression of the acquired immune deficiency syndrome (AIDS), removal of the late-phase infected cells may be critical (Science 1996; 272: 1962). However, there has been no compounds which display a selective removal of HIV-1 itself and HIV-1-infected cells, although a vast number of anti-HIV-1 chemotherapeutic candidates have been described. Similarly, although there have been a various reports which described the anti-HIV-1 effects of a variety of anti-oxidants (FEBS Letters 1988; 236: 282-286, AIDS Res Human Retroviruses 1990; 7: 919-927, Proc Natl Acad Sci USA 1990; 87: 4884-4888, Proc Natl Acad Sci USA 1991; 88: 986-990), no such compound was reported to block acute HIV-1 infection.
The .gamma.-L-glutamyl-L-cysteine ester compound of formula (I): ##STR2##
wherein R is a straight chain, branched or cyclic hydrocarbon group having 1-10 carbon atoms, or a straight chain or branched hydrocarbon group having 1-5 carbon atoms substituted with an aromatic group; or the oxidized dimer obtained by dehydrogenation between two .gamma.-L-glutamyl-L-cysteine esters having formula (I), is known as an anti-oxidant, working either directly or as a unique GSH pro-drug, thereby performing preventive or therapeutic effects against liver disease, cataracts, kidney disease, heart and liver reperfusion injury, arrhythmia, and lung disease, such as asthma, caused by active oxygen and free radical injury (WO 88/00182 (.fwdarw.U.S. Pat. No. 4,927,808) and WO 92/18420 (.fwdarw.U.S. Pat. No. 5,631,234)). In particular, .gamma.-L-glutamyl-L-cysteine ethyl ester (.gamma.GCE) has been reported to be effective against cataracts (Ophthalmic Res 1991; 23: 51-58), hepatic injury (Res Corn Chem Pathol Pharmacol 1993; 82: 49-64), heart and liver reperfusion injury (Brit J Pharmacol 1991; 104: 805-810, J Am Coll Cardiol 1994; 24: 1391-1397, Circulation Res 1994; 74: 806-816, and, Transplantation 1992:54: 414-418) and asthma (Am Rev Respir Dis 1992; 145: 561-565). Howvever, there is not a report on the effects of .gamma.-L-glutamyl-L-cysteine ester compound against HIV infection.